2010-01-13Zeitschriftenartikel DOI: 10.1002/art.27316
HLA–B27 heavy chains distinguished by a micropolymorphism exhibit differential flexibility
Objective: Although the products of the HLA subtypes B*2705 and B*2709 differ only in residue 116 (Asp versus His) within their peptide-binding grooves, they are differentially associated with inflammatory rheumatic diseases such as ankylosing spondylitis (AS): B*2705 occurs in AS patients, whereas B*2709 is only rarely encountered. The reasons for this distinct association are still unclear but could include subtypespecific conformational and dynamic properties of these antigens. The present study was undertaken to investigate structural and dynamic differences between B*2705 and B*2709 and their possible relationship to subtypespecific disease association. Methods: The membrane-distal segments of the B*2705 and B*2709 heavy chains were expressed in vitro and reconstituted together with ß2-microglobulin and a peptide. HLA–B27 complexes loaded with 2 self peptides (TIS [RRLPIFSRL] and pVIPR [RRKWRRWHL]) and a sequence-related viral peptide (pLMP2 [RRRWRRLTV]) were studied by isotope-edited infrared spectroscopy to detect differences in their structure and flexibility at physiologic temperature. Results: Our analyses revealed the existence of subtype-specific conformational differences between the 2 HLA–B27 heavy chains at physiologic temperature, which are undetectable using x-ray crystallography. Irrespective of the bound peptide, the heavy chain of the B*2705 complex exhibited higher conformational flexibility than the B*2709 heavy chain. Conclusion: The present study demonstrates the existence of previously undetected systematic conformational and dynamic differences between the heavy chains of the 2 HLA–B27 subtypes. Since effector cell recognition of cells expressing HLA antigens is dependent on the dynamic properties of the interacting cell surface molecules, this HLA–B27 subtype–specific heavy chain flexibility could have a role in the distinct association of HLA–B27 subtypes with spondylarthritides.
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